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Transplantation in the ‘New Thalassemia Era’: Has BMT Improved as Much as Chelation? How Will It Relate to Gene Therapy?

Children born with thalassemia experience toxicly high level of iron in the bodies, since their deformed red blood cells are not able to make use of the iron. For this reason, life-long treatment of thalassemia has included a process known as “chelation” where iron is removed from the blood via blood transfusion.
It is only recently that chelation has been made possible via a pill, “oral chelation.” Major advances in the field of oral iron chelators have heralded a "new thalassemic era" in which individuals with severe thalassemia having access to appropriate supportive care may enjoy long and productive lives. This type of continuing care, however, is often not available or not accessible to most children in low- and middle-income countries (LMICs).
In parallel, also bone marrow (hematopoietic stem cell) transplantation (BMT), the only established modality providing definitive cure, is becoming increasingly safe, widely applicable, and cost-effective. Unfortunately, however, it is impossible to compare side-by-side continuing care with BMT because the follow-up required, at least 20-30 year, would make study results obsolete and irrelevant by the time the information becomes available.
What is a bone marrow transplant?
A blood and marrow stem cell transplant is a procedure that replaces a person's faulty stem cells with healthy ones.
Stem cells are found in bone marrow, a spongy tissue inside the bones. Stem cells develop into the three types of blood cells that the body needs:

  • Red blood cells, which carry oxygen throughout the body
  • White blood cells, which fight infections
  • Platelets (PLATE-lets), which help the blood clot

Small numbers of stem cells also are found in the blood and in the umbilical cord (the cord that connects a fetus to its mother's placenta). Another type of stem cell, called an embryonic (em-bre-ON-ik) stem cell, can develop into any type of cell in the body. These cells aren't found in bone marrow.
By replacing a person’s faulty stem cells with healthy ones, they are now able to produce healthy red blood cells and be cured of thalassemia. BMT plays a great role in improving the quality of life for both patients and their families through decreasing medical, psychological and financial burdens of conventional continuous treatment.

The Results
The cumulative experience on close to 3,000 BMTs done for severe thalassemia in the past 30 years has consolidated outcomes of over 90% in selected young low-risk patients (age < 7 years with no hepatomegaly) with a histocompatible family donor1, even in LMICs2. BMT is also associated with improved quality of life and is increasingly cost-effective. The major long-term side effect of BMT is infertility, which can occur in over 60% of cases, while growth post-BMT as well as secondary malignancies has not been a major issue.
Being able to insert a normal hemoglobin gene complex into autologous hematopietic stem cells would be the ultimate solution. However, because of technical complexities, concerns about oncogenicity, regulatory issues and costs, this field has moved very lowly with only two patients treated so far, one in July 2007 and the other in November 20123. The first one, a 18 year old with EIBO severe thalassemia intermedia who has shown B-globin vector-bearing cells 6 months after autologous transplantation and achieved a stable hemoglobin in the 8.5-9 g/dL level. In order to promote the engraftment of the gene-modified autologous transplant, however, administration of a myelotoxic therapy was required so that the risk of infertility, the major side effect of BMT, may be substantial also after gene therapy.
A major leap forward in terms of universal BMT applicability is coming from the successful use of partially matched related donors (e.g. mother or father).4,5 This option may actually be the ultimate standard gene therapy will have to confront in terms of safety, efficacy, applicability and costs.
Article by Lawrence Faulkner, Medical Coordinator, Cure2Children, Florence, Italy
1. Angelucci, E. Hematopoietic Stem Cell Transplantation in Thalassemia. Hematology 456-462 (2010). doi:l 0.'1182/asheducation-201 0.1.456
2. Mehta, P. A. & Faulkner, L. B. Hematopoietic Cell Transplantation forThalassemia: A Global Perspective. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 19(1 Suppl), S70-3 (2013).
3. Payen, E. & Leboulch, P. Advances in stem cell transplantati<?n and gene therapy in the p-hemoglobinopathies. Ash Educ. Program Book 2012,276-283 (2012).
4. Sodani, P. et al. Transplantation from haploidentical mother to child with thalassemia Purified T-depleted, CD34+ peripheral blood and bone marrow cell. Blood 115, 1296-1302 (2010).
5. Bolanos-Meade, J. et al. HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood (2012). doi:l 0.1182/blood-2012-07-438408


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